Aneurysmal Subarachnoid Hemorrhage
Conditions
Brief summary
The LD-ITUK is a multicenter, prospective, randomized, double-blind, blind endpoint, placebo-control design trial. All eligible patients with the diagnosis of severe aSAH will be randomly assigned to the treatment group or the placebo group. Patients in the treatment group will receive standard treatment with the addition of lumbar drainage combined with intrathecal urokinase injection started within 24 hours after aneurysm treatment with 30000 IU urokinase, once a day for 3 consecutive days. Patients in the control group will receive standard treatment with the addition of lumbar drainage combined with intrathecal placebo (0.9%NaCl) injection. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 2 on the modified Rankin Scale (mRS), at 6 months after aneurysmal SAH. Primary outcome will be determined by a member of the Independent Committee on Terminal events.
Detailed description
Aneurysmal subarachnoid hemorrhages (aSAH) represent about 8% of all strokes and 9.8 per 100,000 per year in China, which is higher than the overall annual incidence rate worldwide. The cumulative death rate after-onset represent about 24.6% in China, only about 30% survivors will be able to have a good neurological prognosis, the majority of the remaining survivors suffer from long-term disability or cognitive impairment. However, these condition may be even worse in patients with severe aSAH. Studies suggest that early clearance of subarachnoid clot may be associated with a good neurological prognosis. Indeed, subarachnoid clot aggravate the phenomena of cerebral vasospasm and delayed cerebral ischemia in the delayed phase, and promote cell injure within the hypoperfusion zone of the brain in the longer term. Thus, early removal of subarachnoid clot may have a favorable effect on neurological prognosis. Current aSAH recommendations and guidelines advocate the use of lumbar drainage only in case of acute hydrocephalus. The EARLYDRAIN trial suggests that lumber cerebrospinal fluid drainage can early remove subarachnoid clot compare to the standard neurocritical treatment, and improve the prognosis after aSAH. However, the ratio of unfavorable prognosis in severe aSAH is still high. Intrathecal urokinase injection has been proved to effeciently remove the subarachnoid clot, however, no randomized control trials have been conducted to evaluate the improvement of lumbar drainage combined with intrathecal urokinase injection in the favorable functional outcome, defined as a score of 0 to 2 on the modified Rankin Scale (mRS), at 6 months after aneurysmal SAH. The LD-ITUK trial was designed to evaluate whether severe aSAH treated by standard treatment with the addition of lumbar drainage combined with intrathecal urokinase injection have a significantly higher percentage of favourable outcome after six months (score 0-2 on the Modified Rankin Scale) compared to the placebo treated by standard treatment with the addition of lumbar drainage combined with intrathecal placebo (0.9%NaCl) injection.
Interventions
DRUGUrokinase
On the basis of standard treatment for severe neurological conditions, within 24 hours of aneurysm treatment, lumbar drainage combined with intrathecal urokinase injection was started. 30,000 IU urokinase dissolved in 3 ml normal saline was injected into the subarachnoid space, 3 ml normal saline was rinsed into the tube, and the tube was clamped for observation for 2 hours, once a day, for 3 consecutive days. Lumbar cisternae drainage Cerebrospinal fluid is slowly and steadily drained at a rate of less than 8ml/h per hour, the daily drainage volume is not more than 200 ml, and the drainage time of lumbar cisternae is controlled within 7 to 10 days, not more than 14 days.
DRUGPlacebo
On the basis of standard treatment for severe neurological conditions, the treatment of lumbar drainage combined with intrathecal placebo saline injection was started within 24 hours after aneurysm treatment, 3 ml placebo was injected into the subarachnoid space, 3 ml normal saline was flushed into the tube, and the tube was observed for 2 hours, once a day for 3 consecutive days. Lumbar cisternae drainage Cerebrospinal fluid is slowly and steadily drained at a rate of less than 8ml/h per hour, the daily drainage volume is not more than 200 ml, and the drainage time of lumbar cisternae is controlled within 7 to 10 days, not more than 14 days.
Sponsors
Second Affiliated Hospital of Nanchang University
First Affiliated Hospital of Fujian Medical University
Huashan Hospital
Henan Provincial People's Hospital
Tongji Hospital
Southern Medical University, China
Qilu Hospital of Shandong University
Sichuan Provincial People's Hospital
Zhongnan Hospital
Zhejiang University
The First Affiliated Hospital of Zhengzhou University
Xiangya Hospital of Central South University
First Affiliated Hospital of Gannan Medical University
Ganzhou City People's Hospital
The First Affiliated Hospital of Anhui Medical University
Renmin Hospital of Wuhan University
First Affiliated Hospital of Harbin Medical University
The Second Affiliated Hospital of Harbin Medical University
Yichang Central People's Hospital
Xianning Central Hospital
Linyi People's Hospital
Panzhihua Central Hospital
Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University
The Second Military Medical University Changhai Hospital
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
The First Affiliated Hospital with Nanjing Medical University
904th Hospital of the Joint Logistics Support Force of the PLA
Qianfoshan Hospital
Dezhou Hospital Qilu Hospital of Shandong University
Liaocheng People's Hospital
Xuanwu Hospital, Beijing
Jiujiang No.1 People's Hospital
The First People's Hospital of Changde City
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient's age ≥ 18 years * First occurrence of aneurysmal subarachnoid hemorrhage * Patients without any craniotomy treatment before onset * Hunt-Hess grade III-V * mRS grade 0 or 1 before onset * Aneurysm treatment within 48 hours of onset * Informed consent given by the subject or guardian
Exclusion criteria
* Subarachnoid hemorrhage caused by arteriovenous malformation or moyamoya disease or other cerebrovascular disease * Patients requiring craniotomy to remove intracranial hematoma * modified Fisher Scale grade 0 * Prothrombin time (PT) and activated partial thromboplastin time (APTT) are greater than 2 times the extended range * Absolute contraindications for lumbar puncture (e.g., brain hernia, puncture site infection) * Patients with a life expectancy of less than 1 year due to other causes * Other concomitant serious diseases that are difficult to treat; * Pregnant woman * Patients who were known to be allergic to urokinase and excipients or had a history of severe allergy and were deemed unsuitable for inclusion by the investigators * Participated in another interventional clinical trial within 30 days before randomization * Other reasons deemed unsuitable for study participation by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale (mRS) | 180 days | Good (mRS 0-2) and Poor (mRS 3-6) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale (mRS) | 90 days | Good (mRS 0-2) and Poor (mRS 3-6) |
| Relative Modified Rankin Scale (mRS) | 90 days, 180 days | Good (mRS 0-3) and Poor (mRS 4-6) |
| Modified Rankin Scale (mRS) distribution | 180 days | On the distributed proportion in scores (0-6) on the mRS |
| Glasgow Outcome Scale (GOS） | 180 days | Good (GOS 4-5) and Poor (GOS 1-3) |
| Questionnaire EuroQol Five Dimensions Questionnaire (EQ-5D) | 180 days | EQ-5D questionnaires have 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression" and all dimensions are described by 3 problem levels corresponding to patient response choices. |
| Barthel Index for Activities of Daily Living (BI) | 180 days | The Barthel Index (BI) measures the extent to which somebody can function independently and has mobility in their activities of daily living (ADL) i.e. feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair transfer, ambulation and stair climbing. |
| Total hospitalized time | Discharge (assessed up to 30 days) | Toal hospitalized time from ofter-onset to discharge, including neurocritical care unit |
| Total hospitalized costs | Discharge (assessed up to 30 days) | Toal hospitalized costs from ofter-onset to discharge |
| Cerebral vasospasm (CV) | 14 days | Occurence of any symptomatic or image CV after aSAH |
| Delayed cerebral ischemia (DCI) | 14 days | Occurence of any symptomatic or image DCI after aSAH |
| Death | 180 days | Occurence of any death during follow-up after operation |
| Hydrocephalus | 180 days | Occurence of a hydrocephalus after-onset |
| Rebleeding | 30 days | Occurence of a rebleeding after-onset |
Countries
China
Contacts
CONTACTXingen Zhu, MS
PRINCIPAL_INVESTIGATORXingen Zhu, MS
Second Affiliated Hospital of Nanchang University
Outcome results
None listed